Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study

Eur J Vasc Endovasc Surg (2016)

-,

1e10

Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study A. Velescu

a,b,c

, A. Clara

a,b,c

, J. Peñafiel d, M. Grau d, I.R. Degano d, R. Martí e, R. Ramos

e,f

, J. Marrugat d, R. Elosua

d,*

a

Angiology and Vascular Surgery Department, Hospital del Mar, Barcelona, Spain IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain Universitat Autònoma de Barcelona, Spain d Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain e Research Unit, Family Medicine, Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol), Girona, Spain f TransLab Research Group, Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain b c

WHAT THIS PAPER ADDS This is the largest epidemiological study to date assessing the incidence of objectively diagnosed peripheral arterial disease (PAD) in a general population. The results indicate low incidence of lower extremity PAD in the Mediterranean area and suggest that the leading risk factors are diabetes in patients younger than 66 years and smoking in the older population.

Objectives: The reported incidence of lower extremity peripheral arterial disease (PAD) in Western countries ranges between 530 and 2,380 per 100,000 person years. The aims of this study were to determine the incidence of PAD and identify associated risk factors in a Mediterranean population. Methods: Cardiovascular risk factors, the Edinburgh questionnaire, and ankle brachial index (ABI) were collected from 5,434 individuals, aged 35e79 years, from a population based cohort study at baseline and after a mean of 5.7 years follow up. PAD was defined as ABI <0.9 or a clinical diagnosis during follow up. Logistic and regression tree analyses were used to identify factors associated with PAD. Results: In total, 118 new cases of confirmed PAD were identified. The cumulative population incidence rate of PAD was 377 cases per 100,000 person years. For symptomatic PAD, this figure was 102 per 100,000 person years. The most important risk factors for PAD were current (OR 2.30; 95% CI 1.27e4.16) or former smoking (OR 2.02; 95% CI 1.19e3.43), diabetes (OR 1.78; 95% CI 1.17e2.72), age (OR 1.04; 95% CI 1.02e1.07), history of cardiovascular disease (OR 2.06; 95% CI 1.22e3.51), triglycerides level (OR 1.56; 95% CI 1.07e2.29), and systolic blood pressure (OR 1.02; 95% CI 1.01e1.03). In the population
65 years the most relevant risk factor was diabetes, whereas in those >65 years smoking was the leading factor. Long-term uncontrolled diabetes was the strongest risk factor for PAD (OR 10.14; 95% CI 3.57e28.79). Conclusion: The incidence of lower extremity PAD is lower in the Mediterranean area than has been reported for other areas. The data suggest that patients with long-term uncontrolled diabetes and former and current smokers older than 65 years should be considered for PAD screening. Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 18 August 2015, Accepted 29 December 2015, Available online XXX Keywords: Ankle brachial index, Peripheral arterial disease

INTRODUCTION Peripheral arterial disease (PAD) is one of the three main clinical manifestations of atherosclerosis.1 PAD is a well known cause of functional limitation and deterioration of * Corresponding author. Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. E-mail address: [email protected] (R. Elosua). 1078-5884/Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2015.12.045

quality of life. It is also the primary cause of lower limb amputation2 in Western countries and an independent risk factor for coronary and cerebrovascular events and all cause mortality.3 The epidemiology of PAD has received little attention in the past compared with other manifestations of atherosclerosis. The prevalence of PAD in Western populations ranges from 6.3% to 21.4% depending on PAD definition, sex, and age range.4e7 In a previous study8 a prevalence of PAD of 4.5% (5.2% in men and 3.9% in women) in the REGICOR study population was reported, showing a lower prevalence of PAD in the Mediterranean area. A number of studies have assessed the incidence of PAD in different

Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

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Western populations9e15 and specifically in the Mediterranean area.16,17 The reported incidence of PAD ranges from 530 to 2,380 per 100,000 person years depending on the population, screening test, age range, and sex.9,16 It was hypothesized that the incidence of PAD in the Girona province of northeastern Spain is also lower than in other populations. One limitation of these studies is that only a few of them10,11,15e17 have used an objective test to screen for the disease. PAD is usually asymptomatic before evolving to clinical stages, such as intermittent claudication or critical limb ischemia. In this asymptomatic phase, which accounts for at least 50% of patients, PAD can only be reliably detected by non-invasive tests such as the ankle brachial index (ABI) performed with a sphygmomanometer and a Doppler device, having a sensitivity of 90% and a specificity of 95%.18 An ABI between 0.9 and 1.4 is generally considered normal; a lower value suggests the presence of lower extremity PAD and a higher value suggests a noncompressible calcified vessel. Although the risk factors associated with PAD are those already known to be associated with other atherosclerotic diseases, the magnitude of the effect of these risk factors could vary in the different clinical manifestations of atherosclerosis and even within subsets of patients suffering from PAD. Progress in clarifying these questions has been hampered by the limited sample size of PAD epidemiological studies that have used objective methods to screen the disorder.10,11,15e17 The aims of this study were to determine the annual incidence of lower extremity PAD, assess the magnitude of the association between the classical risk factors and PAD, and evaluate whether changes in the presence and control of these risk factors are associated with PAD incidence in a large sample of a general Mediterranean population with low incidence of cardiovascular disease.19 METHODS Study design and population A prospective population-based cohort study was carried out in Girona province (w700,000 inhabitants) in northeastern Spain (REGICOR, REgistre GIroni del COR; which stands for the Girona Heart Registry). Individuals living in the city of Girona and three surrounding rural villages were randomly selected from the nearest census and invited to participate. Recruited participants were aged 35e79 years, had lived in the referral area for at least 6 months, were free of terminal disease, and were not institutionalized. Selected participants were contacted by post, informing them of the aims of the study and the tests to be performed. Participants were asked to fast for at least 10 hours before their appointment at the health centre; a telephone number for inquiries was also supplied. Participants who provided a phone number were contacted 1 week before the examination to confirm attendance. A total of 6,352 participants were recruited and examined from 2003 to 200620 (participation rate 73.8%), with a second physical

A. Velescu et al.

examination between 2009 and 2014. For the present study, participants aged 35e79 years were selected, with a normal ABI at the beginning of the study and follow up through to the end of the study. The local ethics committee approved the study protocol and all the participants gave signed informed consent. Baseline and follow up measurements Examinations were performed by trained nurses using standardized measurement methods and validated MONICA questionnaires at both visits.21,22 The MONICA smoking questionnaire was used to evaluate cigarette consumption, and participants were classified as smokers (current or quit < 1 year), former smokers (quit  1 year), or never smokers. A standardized questionnaire was used to collect self reported educational level as an indicator of socioeconomic position. Three educational levels were defined: elementary school, secondary school, and university degree. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2). Waist circumference was measured midway between the lowest rib and the iliac crest in the horizontal position after the patient exhaled while standing. Readings were rounded up to the nearest 0.5 cm. Patients were considered hypertensive if previously diagnosed by a physician, under treatment, or presenting with systolic blood pressure (SBP)  140 mmHg or diastolic blood pressure (DBP)  90 mmHg. Hypertension control was defined as previous diagnosis or under treatment and SBP < 140 mmHg and DBP < 90 mmHg. Fasting blood samples were taken and total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, and glucose concentrations were determined. Diabetes was defined as history of diabetes, diabetes treatment or fasting glucose 126 mg/dL. Glycated hemoglobin (HbA1c) was recorded from medical records at the beginning of the study and at the end of the follow up (6 months of the visit date) to assess diabetic control. Diabetic control was defined as previous diagnosis or under treatment and HbA1c < 7%. Baseline and follow up ankle brachial index measurements The ABI was measured by nurses trained by a senior vascular surgeon using a standardized methodology.8 After 5 minutes of rest, SBP was measured in the brachial artery in both arms, with a continuous Doppler device (SONICAID 421, Oxford instruments, Abingdon, UK) and an 8 MHz probe. The cuff was then applied to the distal calf, and the Doppler probe was used to determine SBP in the supine position at the right and left posterior and anterior tibial arteries. The ABI was calculated as the ratio of the systolic pressure in the tibial arteries to the highest brachial systolic pressure. The lowest ABI value obtained from the left and the right ankle was used for analysis. A protocol of independent measurements assessed operator performance and found low inter- and intra-operator variability, showing an intraclass correlation coefficient of 0.92 and 0.94, respectively.

Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

PAD in the REGICOR Study

Follow up All participants were invited to attend a second physical examination during 2009e2014. Participants who were institutionalized or had moved from the area were excluded. At this follow up visit, the participants’ comorbidities were recorded, a second ABI measurement was performed following the same protocol used in the baseline visit, and the Edinburgh questionnaire was administered.23 Symptomatic clinical claudication was assessed based on participants’ answers to this questionnaire: 1. Do you get any pain or discomfort in your legs when you walk? 2. Does this pain ever occur when you are standing still or sitting? 3. Do you get this pain if you walk uphill or hurry? 4. Do you get this pain if you walk at an ordinary pace on level ground? 5. What happens to the pain if you stand still? 6. Does the pain disappear within 10 minutes or less when you stand still? 7. Where do you get the pain or discomfort? (leg diagram presented) Based on the response, participants were considered to present symptomatic clinical claudication when they answered questions 1, 3, 4, and 6 (which encompasses question 5) affirmatively, question 2 negatively, and marked the calf, thigh and/or buttock area on the diagram (question 7). Participants with a normal ABI and no symptoms of claudication but with a medical history of intervention for PAD (angioplasty/bypass surgery) were also included in the confirmed and symptomatic PAD group. In those participants who did not attend the follow up physical examination, the presence of PAD was assessed by reviewing medical records and the mortality register (ICD9 codes: 440.2, 440.8, 440.9; ICD10 codes: I70.2, I70.8, I70.9).

Peripheral arterial disease definition The following criteria were used to define PAD: 1. Confirmed PAD: (a) participants with a pathological ABI at the second examination (<0.9); (b) participants with a clinical diagnosis of PAD recorded in the medical history confirmed with an objective test of the diagnosis (ABI < 0.9, diagnostic imaging technique); or (c) all fatal events during follow up were reviewed for an objective diagnosis of PAD. All confirmed cases were in turn classified as: e symptomatic: Edinburgh questionnaire indicating clinical claudication or objective clinical signs of PAD in the medical record (surgery or other type of revascularization, amputation, ulcer of vascular origin);

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e asymptomatic: no evidence of clinical claudication on the Edinburgh questionnaire or objective clinical signs of PAD in the medical record. 2. Probable or possible PAD: (a) participants with normal ABI in the beginning and at the end of follow up but presenting a symptomatic clinical claudication by the Edinburgh questionnaire at the end of follow up; or (c) those with a clinical diagnosis of PAD in the medical record but without an objective test confirming this diagnosis.

Statistical analysis The study was powered to detect as statistically significant an odds ratio greater than or equal to 1.3. The assumptions of this estimation were acceptable with the following: an alpha risk of 0.05 and a beta risk of 0.20 in a two sided test, the proportion of events in the non exposed group to be 8%, and a dropout rate of 10% Standard parametric and non-parametric methods were used to compare the characteristics of the participants with confirmed or possible PAD. Several definitions were considered to estimate the incidence of PAD: confirmed PAD as the more strict definition (stratified as symptomatic or asymptomatic), and confirmed and possible PAD as the more permissive definition. The confidence intervals corresponding to the incidence estimations were calculated using a Poisson distribution. The association between risk factors and PAD incidence was evaluated using multivariate logistic regression. A backward elimination procedure was used to select the variables in the final predictive model but forcing the inclusion of age and sex. A regression tree analysis was also performed, which estimates a regression relationship by binary recursive partitioning in a conditional inference framework and identifies in a hierarchical order the variables providing discriminative information and the best cutoff points for those that are continuous.24 To evaluate whether the presence and control of risk factors and changes in their status between baseline and follow up visit were associated with the incidence of PAD, two different strategies were designed: first, data from the baseline examination related to the presence and control of risk factors were used and their association with the incidence of PAD was estimated, including all confirmed cases; second, data from the baseline and follow up examinations related to the presence and control of risk factors were used, and all the potential combinations, and their association with the incidence of PAD was estimated, considering only confirmed asymptomatic cases. In this second approach, symptomatic cases were excluded because these individuals could modify their lifestyle or risk factor control due to the knowledge of the presence of the disease, and this change could bias the estimated association.

Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

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A. Velescu et al.

All analyses were performed using the R statistical package (version 3.1.0, Vienna, Austria).25 A p value < .05 was considered statistically significant. RESULTS From a randomly selected population sample of 6,352 individuals, 5,434 were included in the study. The flow chart defining the exclusion criteria and the type of follow up is shown in Fig. 1. Incidence of PAD The median follow up was 5.76 years, and during this period 118 new cases of confirmed PAD and 161 cases of confirmed or possible PAD were identified. The cumulative incidence of confirmed PAD, symptomatic confirmed PAD, and confirmed or possible PAD, by sex and age group, is shown in Table 1. The incidence increased with age, with an abrupt rise at 65 years followed by stabilization, and was higher in men than in women. The incidence of asymptomatic PAD was almost three times higher than that of symptomatic PAD (Table 1). Risk factors associated with PAD Participant characteristics according to the presence of confirmed PAD are shown in Table 2. The group of participants with PAD was older, with a higher proportion of men, current and former smokers, hypertension, diabetes, statin use, and history of cardiovascular disease (CVD) than those without PAD. The group with PAD also had higher values of SBP, DBP, triglycerides, BMI, and lower HDL cholesterol concentration than the group without PAD. Participant characteristics according to the presence of confirmed PAD

are shown in Table 2, and are also stratified according to the presence or absence of symptoms. The same analysis according to the presence of confirmed or possible PAD is shown in Supplementary Table 1. In the multivariate logistic regression, the variables associated with a higher probability of presenting with confirmed PAD were age, former and current smoking, SBP, triglycerides, diabetes, and history of CVD (Table 3). The same variables were associated with confirmed and possible PAD (Supplementary Table 2). The standardized regression coefficient showed that the most important variables associated with PAD were smoking, diabetes and age (Table 3). The logistic model showed a correct calibration and discrimination for confirmed PAD (area under the curve [AUC] ¼ 0.762) and for confirmed or possible PAD (AUC ¼ 0.760). An analysis was also carried out to determine whether the predictive variables were the same for symptomatic and asymptomatic PAD and showed a similar effect. All the variables showed a similar association pattern except current smoking, which was not associated with symptomatic PAD (Supplementary Table 3). The results of the regression tree analysis showed that the variable most strongly correlated with the incidence of PAD was age. In those participants aged 65 and younger, diabetes and SBP were also correlated with PAD; in those older than 65 the variables with the highest correlation were smoking and SBP (Fig. 2). Accordingly, the logistic regression analyses were stratified by age. In the younger group, the ORs of smoking and diabetes were 1.18 (95% CI 0.63e2.22) and 3.68 (95% CI 1.59e6.93), respectively; in the older group, the ORs were 2.37 (95% CI 1.26e4.47) and 2.02 (95% CI 1.23e3.34), respectively. However, the interactions between age (
65 years or > 65 years) and

REGICOR cohort N = 6,352

Age < 35 = 3 Baseline pathological AB (< 0.9) = 292 Missing ABI = 35 Both ABI > 1.39 = 83 Institutionalized = 193

INCLUDED IN THE STUDY

Moved away from the area = 212

N = 5,434

Medical records/mortality register review (n = 5,434) Physical examination (n = 3,915)

Figure 1. Flow chart of the participants included in this study. ABI ¼ ankle brachial index. Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

PAD in the REGICOR Study

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Table 1. Cumulative incidence rate of peripheral arterial disease by sex and age group (cases per 100,000 person years and 95% CI). Men Confirmed PAD 35e44 y 127 45e54 y 289 55e64 y 350 65e74 y 1326 75e79 y 1610 Total 548 Symptomatic and confirmed PAD 35e44 y 32 45e54 y 105 55e64 y 108 65e74 y 497 75e79 y 222 Total 169 Asymptomatic and confirmed PAD 35e44 y 96 45e54 y 184 55e64 y 243 65e74 y 831 75e79 y 1408 Total 380 Confirmed and possible PAD 35e44 y 159 45e54 y 368 55e64 y 622 65e74 y 1705 75e79 y 2285 Total 760 PAD ¼ peripheral arterial disease.

Women

All

(35e326) (144e517) (186e599) (924e1845) (901e2655) (433e684)

100 108 236 541 376 234

(27e256) (35e252) (113e434) (315e866) (102e963) (167e319)

112 190 289 900 952 377

(48e221) (108e308) (183e434) (672e1180) (573e1487) (312e451)

(1e178) (29e270) (29e276) (265e850) (27e800) (109e252)

25 22 0 159 94 47

(1e139) (1e120) (0e87) (52e371) (2e524) (20e92)

28 59 50 313 153 102

(3e101) (19e138) (14e129) (185e494) (31e446) (70e145)

(13e279) (74e379) (111e461) (521e1259) (750e2408) (285e495)

75 86 236 382 282 187

(15e219) (24e221) (113e434) (197e667) (58e824) (128e265)

84 130 239 588 805 275

(31e183) (65e233) (144e373) (407e821) (460e1308) (220e339)

(52e372) (201e617) (394e933) (1244e2282) (1414e3492) (624e918)

125 108 283 637 1059 311

(41e292) (35e252) (146e495) (389e983) (528e1894) (233e407)

140 225 441 1124 1634 515

(67e258) (135e351) (307e613) (868e1433) (1118e2307) (439e601)

diabetes, and age (
65 years or > 65 years) and smoking were not statistically significant (p ¼ .119 and p ¼ .217, respectively). The results of the analyses of the relevance of risk factor presence and control, and their changes between baseline and follow up visit, are shown in Tables 4 and 5, respectively. From the baseline data it was observed that diabetes was associated with higher risk of PAD, but this risk was much higher among those patients without adequate diabetic control. Moreover, only uncontrolled hypertension was associated with the incidence of PAD. Finally, the groups of former and current smokers show the same effect size of association with PAD (Table 4). It was observed that a long period of uncontrolled diabetes from baseline to follow up was associated with a very high risk of incident PAD (OR ¼ 10.14), and a long period of controlled diabetes showed an effect size similar to the participants included in the non-diabetes group (OR ¼ 0.96) (Table 5). No clear pattern of association was observed for changes in the presence or control of hypertension and the incidence of PAD. Finally, current or former smokers had a higher risk of PAD. Those who were smokers and continued to smoke did not show a higher risk of PAD than the group of “NevereNever” smokers (Table 5). The effect size of the “CurrenteCurrent” category versus the “NevereNever” smoking category by age group (younger than 65 vs. older than 65) was explored, and the magnitude of the

association was very different: a trend to no association was observed in “CurrenteCurrent” younger individuals (OR ¼ 0.71) and a trend to association was observed in “CurrenteCurrent” older individuals (OR ¼ 1.63). However, the interaction between age and smoking groups was not statistically significant. DISCUSSION To the authors’ knowledge, this is the largest epidemiological study to date assessing the incidence of objectively diagnosed PAD in a general population. The incidence of PAD in a region with a low incidence of cardiovascular disease (377 per 100,000 person years) is reported to be less than that reported in other populations (ranging from 530 to 2,380 per 100,000 person years)9e12,14e17 (Table 6). The risk factors associated with the incidence of PAD are those already known to be associated with other atherosclerotic cardiovascular diseases, although the most relevant risk factors, apart from age, were smoking and diabetes. The results here also suggest that smoking is the most important risk factor in older people (>65 years), whereas diabetes is the most important in younger individuals. These results may suggest that different subsets of PAD patients may develop according to their risk factor profile. Finally, the study has allowed the relevance of the presence and control of risk factors, and their changes over

Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

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A. Velescu et al.

Table 2. Baseline participant characteristics according to the incidence of confirmed peripheral arterial disease (PAD), and symptomatic vs. asymptomatic clinical manifestation. PAD p No (n ¼ 5,316) Yes (n ¼ 118) 55.7 (12.2) 64.5 (10.6) <.001 2843 (53.5) 40 (39.9.1) <.001 <.001 2748 (52.2) 41 (35.0) 1352 (25.7) 49 (41.9) 1164 (22.1) 27 (23.7) 2328 (44.5) 83 (70.9) <.001 126 (19.2) 140 (22.6) <.001 79 (10.2) 82 (11.2) .004 211 (41.0) 212 (41.0) .868 136 (36.4) 136 (37.9) .901 53 (13.9) 49 (13.5) .003 94 (69e131) 109 (86e159) <.001

Symptomatic vs. asymptomatic PAD p Symptomatic (n ¼ 32) Asymptomatic (n ¼ 86) 64.3 (9.42) 64.6 (11.1) .917 8 (25.0) 32 (37.2) .304 .277 10 (31.2) 31 (36.5) 17 (53.1) 32 (37.6) 5 (15.6) 22 (25.9) 25 (78.1) 58 (68.2) 1.000 144 (22.2) 139 (22.6) .526 79.6 (9.89) 82.3 (11.4) .201 211 (43.9) 212 (40.2) .931 137 (40.4) 136 (37.1) .983 45 (12.1) 50 (13.9) .080 122 (91; 193) 106 (83; 142) .208

Age, years, mean (SD) Sex, female, n (%) Smoking, n (%) Never Former Current Hypertension, n (%) SBP, mmHg, mean (SD) DBP, mmHg, mean (SD) Total cholesterol, mg/dL; mean (SD) LDL cholesterol, mg/dL, mean (SD) HDL cholesterol, mg/dL, mean (SD) Triglycerides, mg/dL, median (quartile 1 e3) Statin use, n (%) 1064 (20.5) 48 (42.5) <.001 14 (40.7.5) 34 (41.0) .744 Diabetes, n (%) 735 (13.8) 44 (37.3) <.001 15 (46.9) 29 (33.7) .272 Creatinine, mg/dL, mean (SD) 0.89 (0.17) 0.87 (0.17) .594 0.89 (0.17) 0.87 (0.17) .557 BMI*, mean (SD) 27.3 (4.6) 28.4 (4.4) .006 29.4 (4.9) 28.1 (4.2) .200 Waist circumference (SD) 92 (12.8) 97 (12.1) .033 97 (5.8) 97 (13.4) .973 Educational level n (%) <.001 .544 University degree 1222 (23.2) 17 (14.4) 3 (9.4) 14 (16.3) Secondary school 1520 (28.9) 21 (17.8) 7 (21.9) 14 (16.3) Elementary school 2514 (47.8) 80 (67.8) 22 (68.8) 58 (67.4) History of CVD, n (%) 260 (4.9) 22 (18.6) <.001 6 (18.8) 16 (18.6) 1.000 Family history of CVD, n (%) 572 (10.9) 15 (12.9) .591 2 (6.67) 13 (15.1) .348 SD ¼ standard deviation; SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; LDL ¼ low density lipoprotein; HDL ¼ high density lipoprotein; BMI ¼ body mass index; CVD ¼ cardiovascular disease.

time, on the incidence of PAD to be assessed. Diabetic control was the strongest predictor of PAD: those patients with good long-term diabetic control did not show a higher risk of PAD, whereas those with long-term uncontrolled diabetes showed a 10 times higher risk of PAD than participants without diabetes. One of the main problems in comparing the incidence of PAD between different studies is related to the variability of the diagnostic methods and criteria used and the sex and age range of the reference population. Some of the studies used questionnaires only,9,14 whereas others also included objective measurements such as ABI10,11,15e17 or even arteriography.17 This is relevant, as most of the cases are asymptomatic and would not be detected by

questionnaires. In this study, approximately two thirds of the cases were asymptomatic, in accordance with the results reported from other studies.10e12 The incidence of PAD in this study was similar to that reported by Baena-Díez et al.17 and considerably less than that observed by Merino et al.16 (Table 6), both studies that were carried out in an urban Mediterranean area. The study by Merino et al. was undertaken 10 years before this study and included only men aged 55e74 years. These differences could explain the higher rates observed in their study. Higher incidence of PAD has also been reported in other populations, such as the Netherlands,10 Scotland,11 Switzerland,12 and France15 (Table 6). Finally, the observed incidence rate here was similar to that observed in Framingham9 and Quebec14

Table 3. Risk factors associated with the incidence of peripheral arterial disease. Regression coefficient Standardized regression coefficient OR 95% Confidence interval p Age 0.039 0.560 1.04 1.02; 1.07 <.001 Sex, female 0.083 0.099 0.92 0.56; 1.51 .740 Smoking Former 0.703 0.731 2.02 1.19; 3.43 .009 Current 0.833 0.828 2.30 1.27; 4.16 .006 SBP 0.020 0.310 1.02 1.01; 1.03 .001 Ln (triglycerides) 0.445 0.452 1.56 1.07; 2.29 .022 Diabetes 0.577 0.602 1.78 1.17; 2.72 .008 History of CVD 0.723 0.468 2.06 1.22; 3.51 .007 Note. Calibration, HosmereLemeshow: chi square ¼ 13.028; p ¼ .111; Discrimination, area under the ROC curve ¼ 0.762 (95% CI 0.716e 0.808). SBP ¼ systolic blood pressure; CVD ¼ cardiovascular disease. Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

PAD in the REGICOR Study

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Age

≤ 65 years

> 65 years

Diabetes

YES (n = 427) Incidence=0.033

NO

SBP ≤ 159 mmHg (n = 3497) Incidence = 0.008

Smoking

SBP > 159 mmHg (n = 118) Incidence = 0.042

YES (n = 520) Incidence = 0.083

SBP ≤ 188 mmHg (n = 861) Incidence = 0.026

NO

SBP > 188 (n = 11) Incidence = 0.273

Figure 2. Regression-tree analysis of the variables associated with the incidence of confirmed peripheral arterial disease. SBP ¼ systolic blood pressure.

studies (Table 6); however, these studies were conducted 25e30 years ago, only used questionnaires, and could have underestimated the actual incidence, as asymptomatic cases may not have been identified. In summary, the results are in agreement with previous reports from an area with a low incidence of cardiovascular disease. An interesting point is the inconsistency between studies in results related to the association between sex and PAD. The results are in accordance with those of the Framingham study,13 in which the incidence was higher in men than in women. In other populations, however, the incidence is similar or even higher in women than in men.10,15 The study

Table 4. Association between the prevalence and control of cardiovascular risk factors at the baseline visit, and the incidence of symptomatic and asymptomatic peripheral arterial disease.

Age Sex, female Diabetes No diabetes mellitus (n ¼ 4,581) Controlled (n ¼ 648) Uncontrolled (n ¼ 87) Hypertension No HTA (n ¼ 2,900) Controlled (n ¼ 842) Uncontrolled (n ¼ 1486) Smoking Never (n ¼ 2748) Former (n ¼ 1352) Current (n ¼ 1164)

OR 95% Confidence interval 1.05 1.03e1.07 0.79 0.48e1.28

p <.001 .337

Ref. Ref.

Ref.

1.77 1.12e2.80 5.61 2.90e10.82

.015 <.001

Ref. Ref. 1.13 0.63e2.02 1.72 1.08e2.74

Ref. .685 .023

Ref. Ref. 2.04 1.22e3.41 2.07 1.16e3.71

Ref. .006 .014

by Baena-Díez et al.17 showed an incidence rate similar to this study, but contrary to these results they also reported a higher incidence in women than in men. However, the higher incidence in women was only observed in the population younger than 65 years in which few cases were identified, whereas the incidence in the population older than 65 years was twice as high in men as in women. These differences could also be related to population differences in the prevalence of PAD risk factors between sexes, such as smoking. The results of this study identified age, former and current smoking, diabetes, SBP, triglycerides, and personal history of cardiovascular disease as independent risk factors for PAD. These results reinforce the strong association between smoking and PAD that has been consistently reported in other studies10,14e16 and support preventive strategies to reduce smoking prevalence at population level, as it is a modifiable risk factor. As in other studies, diabetes was also strongly associated with PAD.10,14,15 The results suggest that the effect of diabetes on PAD is much more aggressive and rapid than that of smoking, and that the effect of smoking is cumulative and progressive with age. These findings should be confirmed in future studies. The results also suggest that screening for PAD using ABI could be offered to young diabetic patients and the older smoking population. The multiplicative interaction between diabetes and smoking on PAD was also analyzed and it was found that the interaction was not statistically significant. Tapp et al.15 previously reported that the magnitude of the association between smoking and PAD was similar in those who presented with diabetes and those without diabetes. SBP is also a risk factor consistently associated with PAD in most

Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

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Table 5. Association between changes in the prevalence and control of cardiovascular risk factors from baseline to follow up visit and the incidence of asymptomatic peripheral arterial disease. OR

95% Confidence interval 1.07 1.04e1.10 1.07 0.55e2.08

Age Sex, female Diabetes No DMeNo DM (n ¼ 3265) Ref. Ref. No DMeControlled 1.02 0.35e2.96 (n ¼ 190) ControlledeControlled 0.96 0.36e2.53 (n ¼ 226) ControlledeUncontrolled 2.13 0.61e7.44 (n ¼ 57) 3.49 0.75e16.16 UncontrolledeControlled (n ¼ 27) UncontrolledeUncontrolled 10.14 3.57e28.79 (n ¼ 28) Hypertension No HTeNo HT (n ¼ 1745) Ref. Ref. No HTeControlled 1.70 0.56e5.14 (n ¼ 198) 1.58 0.56e4.44 No HTeUncontrolled (n ¼ 301) ControlledeControlled 1.14 0.34e3.80 (n ¼ 328) ControlledeUncontrolled 1.39 0.47e4.12 (n ¼ 230) UncontrolledeControlled 2.36 0.94e5.89 (n ¼ 268) UncontrolledeUncontrolled 1.96 0.86e4.46 (n ¼ 575) Smoking NevereNever (n ¼ 1973) Ref. Ref. FormereFormer (n ¼ 854) 1.96 0.96e4.04 FormereCurrent (n ¼ 48) 5.57 1.09e28.32 CurrenteFormer (n ¼ 242) 3.65 1.45e9.16 CurrenteCurrent (n ¼ 574) 1.08 0.34; 3.40 DM ¼ diabetes mellitus; HT ¼ hypertension.

p <.001 .839 .975 .927 .237 .110 <.001

.348 .388 .826 .555 .067 .110

.067 .039 .006 .901

previous studies.10,14,15 The association between total or low-density lipoprotein cholesterol and PAD is not clear in the literature, having been reported only in one study and mainly related to asymptomatic PAD.5 In this study, triglycerides were the only lipid related variable associated with PAD in the multivariate analysis. This variable has not been analyzed in other studies. Finally, a strong association

between previous history of cardiovascular disease and PAD was observed, which has also been reported by Merino et al.16 Finally, the results of this study highlight the importance of diabetic control in the prevention of PAD. These results are in concordance with recent clinical trials showing that intensive glycemic control in Type 2 diabetes is associated with a lower incidence of cardiovascular disease.26,27 Baseline uncontrolled hypertension was also associated with a higher risk of PAD, again underlining the importance of controlling this risk factor. Finally, current or past exposure to smoking was associated with higher risk of PAD, indicating the significance of avoiding smoking. Strengths and limitations The study is based on a prospective follow up of a population based cohort from an area with low incidence of coronary heart disease. The strengths of this study include the large sample size, an extended follow up period (median 5.7 years), and the assessment of the relevance of the presence and control of several risk factors, and their changes over time, on the incidence of PAD. The ABI measurements were carried out using standardized methods; operators were meticulously trained by a senior vascular surgeon and had a very low intra- and inter-observer variability. However, there might have been misdiagnosis of some PAD in patients with ABI > 1.39 that was considered to be indicative of a calcified artery and was an exclusion criterion for the analyses. A limitation of the study is that most of the cases were asymptomatic and were detected at the follow up visit by the presence of an abnormal ABI. Therefore, the cumulative incidence rate could be determined and logistic regression, instead of Cox survival regression models, was used in the statistical analysis. It must be mentioned that follow up was based on the review of the clinical records without a second ABI measurement in about a quarter (27.95%) of the participants. This differential follow up suggests an underestimation of actual incidence, as most of the cases are asymptomatic. When the impact of these two potential and opposing effects in the sample was analyzed, the incidence of PAD in the whole cohort was 377 events per 100,000 person years whereas in the subgroup of participants attending the follow up visit it was 382 events per 100,000 person years. These differences are very small and the

Table 6. Peripheral arterial disease incidence rates in different populations. Study

Publication year Framingham 1970 Basel 1985 Quebec 1991 Edinburgh 1996 Limburg 2001 Desir 2007 Merino 2010 Baena-Díez 2010

Country

Participants’ age range (years) USA 30e74 Switzerland 35e65 Canada 35e64 Scotland 55e74 Netherlands 40e78 France 30e65 Spain 55e74 Spain 35e84

Sex of included participants Men and women Men and women Men Men and women Men and women Men and women Men Men and women

PAD incidence per 100,000 person years 530 1,080 410 1,550 1,100 766 2,380 484

Please cite this article in press as: Velescu A, et al., Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2015.12.045

PAD in the REGICOR Study

figures presented should be considered valid. However, it is recognized that the exclusion of institutionalized individuals could introduce a bias in the results and the incidence rate could be underestimated, as some individuals could have been institutionalized after major amputation for PAD. Finally, ABI measurements were performed after 5 minutes of rest; in the clinical setting, a 10 minute rest is recommended. The reliability of these measurements was high but the accuracy was not specifically assessed.

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CONCLUSIONS The incidence of cardiovascular disease in this study was lower than in other developed countries. As expected, the majority of the confirmed PAD cases were asymptomatic. The data suggest that diabetes is the most important risk factor in individuals younger than 65 years, whereas smoking is the most relevant in those older than 65 years. Diabetic control is the strongest risk factor associated with new PAD events. The data suggest that patients with longterm uncontrolled diabetes and former and current smokers older than 65 years should be considered for PAD screening. CONFLICT OF INTEREST

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FUNDING This project was funded in part by the following sources: Agència de Gestió Ajuts Universitaris de Recerca: 2014 SGR 240; ISCIII-FIS-FEDER-ERDF: PI11 01801, PI08 1327, PI05 1251, PI05 1297, PI02 0471, FIS99/0013-01, FIS96/0026-01, FIS93/0568, FIS92/0009-05; ISCIII-RETICS-FEDER-ERDF: RD12/0042/0061, RD12/0042/0013, RD06/0009; Agència d’Informació, Avaluació i Qualitat en Salut: AATM 034/33/ 02; Fundació La Marató TV3: 08/1630, and Departament de Salut, Generalitat de Catalunya. IRD was funded by a contract from RecerCaixa (Grant no. RE087465). MG was funded by a contract from Instituto de Salud Carlos III FEDER (FIS CP12/03287).

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APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2015.12.045.

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